Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300.
It has been hypothesized that certain viral infections directly activate a transcription factor(s) which is responsible for the activation of genes encoding type I interferons (IFNs) and interferon-stimulated genes (ISGs) via interferon regulatory factor (IRF) motifs present in their respective promoters. These events trigger the activation of defense machinery against viruses. Here we demonstrate that IRF-3 transmits a virus-induced signal from the cytoplasm to the nucleus. In unstimulated cells, IRF-3 is present in its inactive form, restricted to the cytoplasm due to a continuous nuclear export mediated by nuclear export signal, and it exhibits few DNA-binding properties. Virus infection but not IFN treatment induces phosphorylation of IRF-3 on specific serine residues, thereby allowing it to complex with the co-activator CBP/p300 with simultaneous nuclear translocation and its specific DNA binding. We also show that a dominant-negative mutant of IRF-3 could inhibit virus-induced activation of chromosomal type I IFN genes and ISGs. These findings suggest that IRF-3 plays an important role in the virus-inducible primary activation of type I IFN and IFN-responsive genes.
Yoneyama
M
M
Department of Tumor Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Japan.
Suhara
W
W
Fukuhara
Y
Y
Fukuda
M
M
Nishida
E
E
Fujita
T
T
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D006801:Humans; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009522:Newcastle disease virus / Q000502:physiology; D056921:Nuclear Receptor Coactivator 3; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3